US6897315B2 - Method for producing 8-methoxy-quinolinecarboxylic acids - Google Patents
Method for producing 8-methoxy-quinolinecarboxylic acids Download PDFInfo
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- US6897315B2 US6897315B2 US10/406,129 US40612903A US6897315B2 US 6897315 B2 US6897315 B2 US 6897315B2 US 40612903 A US40612903 A US 40612903A US 6897315 B2 US6897315 B2 US 6897315B2
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 8
- RAZRTJLTLNPWKV-UHFFFAOYSA-N 8-methoxyquinoline-2-carboxylic acid Chemical class C1=C(C(O)=O)N=C2C(OC)=CC=CC2=C1 RAZRTJLTLNPWKV-UHFFFAOYSA-N 0.000 title 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 72
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 50
- 238000000034 method Methods 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 21
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 17
- -1 FCH2—CH2— Chemical group 0.000 claims description 15
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 12
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 8
- 229910052700 potassium Chemical group 0.000 claims description 8
- 239000011591 potassium Chemical group 0.000 claims description 8
- 125000001931 aliphatic group Chemical group 0.000 claims description 6
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 6
- 238000009835 boiling Methods 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 4
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- UBIKHJZIEKPIBU-UHFFFAOYSA-N 3-oxo-2h-quinoline-2-carboxylic acid Chemical class C1=CC=CC2=CC(=O)C(C(=O)O)N=C21 UBIKHJZIEKPIBU-UHFFFAOYSA-N 0.000 claims 1
- 239000003242 anti bacterial agent Substances 0.000 abstract description 4
- 229940088710 antibiotic agent Drugs 0.000 abstract description 4
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 3
- 230000003389 potentiating effect Effects 0.000 abstract description 3
- RDVMFJRDNHJAMN-UHFFFAOYSA-N 8-methoxy-3-oxo-2h-quinoline-2-carboxylic acid Chemical class O=C1C(C(O)=O)N=C2C(OC)=CC=CC2=C1 RDVMFJRDNHJAMN-UHFFFAOYSA-N 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 238000010992 reflux Methods 0.000 description 13
- IDIIJJHBXUESQI-DFIJPDEKSA-N moxifloxacin hydrochloride Chemical compound Cl.COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 IDIIJJHBXUESQI-DFIJPDEKSA-N 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 10
- 0 [1*]N1C=C(C(=O)O)C(=O)C2=C1C(C)=C(N(C)C)C(F)=C2[3*] Chemical compound [1*]N1C=C(C(=O)O)C(=O)C2=C1C(C)=C(N(C)C)C(F)=C2[3*] 0.000 description 8
- GETQZCLCWQTVFV-UHFFFAOYSA-N CN(C)C Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 6
- FABPRXSRWADJSP-MEDUHNTESA-N [H]N1CCC[C@@]2([H])CN(C3=C(OC)C4=C(C=C3F)C(=O)C(C(=O)O)=CN4C3CC3)C[C@@]12[H] Chemical compound [H]N1CCC[C@@]2([H])CN(C3=C(OC)C4=C(C=C3F)C(=O)C(C(=O)O)=CN4C3CC3)C[C@@]12[H] FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- ZRLVQFQTCMUIRM-UHFFFAOYSA-N potassium;2-methylbutan-2-olate Chemical compound [K+].CCC(C)(C)[O-] ZRLVQFQTCMUIRM-UHFFFAOYSA-N 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- ZOCSBJTWWJARJQ-UHFFFAOYSA-N 8-methoxy-2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=C(C(O)=O)C(=O)NC2=C1C=CC=C2OC ZOCSBJTWWJARJQ-UHFFFAOYSA-N 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- WEXQOLCYKFJAJZ-ZUZCIYMTSA-N [H]N1CCC[C@@]2([H])CN(C3=C(F)C4=C(C=C3F)C(=O)C(C(=O)O)=CN4C3CC3)C[C@@]12[H] Chemical compound [H]N1CCC[C@@]2([H])CN(C3=C(F)C4=C(C=C3F)C(=O)C(C(=O)O)=CN4C3CC3)C[C@@]12[H] WEXQOLCYKFJAJZ-ZUZCIYMTSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 4
- 150000004682 monohydrates Chemical class 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical group C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 description 3
- VFPSRSZPYQYBGF-UHFFFAOYSA-N CCC(C)(C)OC.COC(C)(C)C Chemical compound CCC(C)(C)OC.COC(C)(C)C VFPSRSZPYQYBGF-UHFFFAOYSA-N 0.000 description 3
- QQDIQXZJCOJVQR-UHFFFAOYSA-N CCC(C)(C)OCC(C)(C)OC Chemical compound CCC(C)(C)OCC(C)(C)OC QQDIQXZJCOJVQR-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- RPHLUJOQGYWPIF-OAPXFOCYSA-N 7-[(4as,7as)-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl]-1-cyclopropyl-6-fluoro-8-methoxy-3,4-dioxo-2h-quinoline-2-carboxylic acid;hydrochloride Chemical compound Cl.C1=2C(OC)=C(N3C[C@H]4NCCC[C@H]4C3)C(F)=CC=2C(=O)C(=O)C(C(O)=O)N1C1CC1 RPHLUJOQGYWPIF-OAPXFOCYSA-N 0.000 description 2
- APGCVOFJTSOEQP-UHFFFAOYSA-N C.CCC(C)(C)OC.COC(C)(C)C Chemical compound C.CCC(C)(C)OC.COC(C)(C)C APGCVOFJTSOEQP-UHFFFAOYSA-N 0.000 description 2
- QXKHYNVANLEOEG-UHFFFAOYSA-N Methoxsalen Chemical group C1=CC(=O)OC2=C1C=C1C=COC1=C2OC QXKHYNVANLEOEG-UHFFFAOYSA-N 0.000 description 2
- LBIDHBYCTAZWKZ-YVEFUNNKSA-N [H]N1CCC[C@@]2([H])CN(C3=C(C)C4=C(C=C3F)C(=O)C(C(=O)O)=CN4C3CC3)C[C@@]12[H] Chemical compound [H]N1CCC[C@@]2([H])CN(C3=C(C)C4=C(C=C3F)C(=O)C(C(=O)O)=CN4C3CC3)C[C@@]12[H] LBIDHBYCTAZWKZ-YVEFUNNKSA-N 0.000 description 2
- 229960003237 betaine Drugs 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 1
- GROVYFNLHSHFIP-VXEGYDISSA-N CC1CN(C)CCN1C.CCN1CCN(C)CC1.CN(C)C.CN1CCC(=NO)CC1.CN1CCC(N)CC1.CN1CCN(C)CC1.CN1CC[C@](CN)(CF)C1.CN1C[C@@H](N)C2(CC2)C1.CN1C[C@H](CN)[C@@H](C(F)(F)F)C1.CNC1CCCN(C)C1.CO/N=C1/CN(C)CCC1CN.[H]N1C(C)CN(C)CC1C.[H]N1CCN(C)CC1.[H]N1CCN(C)CC1C.[H][C@@]12CN(C)C[C@]1(C)C[C@@H]2N.[H][C@@]12CN(C)C[C@]1([H])[C@H]2N Chemical compound CC1CN(C)CCN1C.CCN1CCN(C)CC1.CN(C)C.CN1CCC(=NO)CC1.CN1CCC(N)CC1.CN1CCN(C)CC1.CN1CC[C@](CN)(CF)C1.CN1C[C@@H](N)C2(CC2)C1.CN1C[C@H](CN)[C@@H](C(F)(F)F)C1.CNC1CCCN(C)C1.CO/N=C1/CN(C)CCC1CN.[H]N1C(C)CN(C)CC1C.[H]N1CCN(C)CC1.[H]N1CCN(C)CC1C.[H][C@@]12CN(C)C[C@]1(C)C[C@@H]2N.[H][C@@]12CN(C)C[C@]1([H])[C@H]2N GROVYFNLHSHFIP-VXEGYDISSA-N 0.000 description 1
- MJKLCALMCCHQBO-MHRMMSPVSA-N CC1CN(C)CCN1C.CCN1CCN(C)CC1.CN1CCC(=NO)CC1.CN1CCC(N)CC1.CN1CCN(C)CC1.CN1CC[C@](CN)(CF)C1.CN1C[C@@H](N)C2(CC2)C1.CN1C[C@H](CN)[C@@H](C(F)(F)F)C1.CNC1CCCN(C)C1.CO/N=C1/CN(C)CCC1CN.[H]N1C(C)CN(C)CC1C.[H]N1CCN(C)CC1.[H]N1CCN(C)CC1C.[H][C@@]12CN(C)C[C@]1(C)C[C@@H]2N.[H][C@@]12CN(C)C[C@]1([H])[C@H]2N Chemical compound CC1CN(C)CCN1C.CCN1CCN(C)CC1.CN1CCC(=NO)CC1.CN1CCC(N)CC1.CN1CCN(C)CC1.CN1CC[C@](CN)(CF)C1.CN1C[C@@H](N)C2(CC2)C1.CN1C[C@H](CN)[C@@H](C(F)(F)F)C1.CNC1CCCN(C)C1.CO/N=C1/CN(C)CCC1CN.[H]N1C(C)CN(C)CC1C.[H]N1CCN(C)CC1.[H]N1CCN(C)CC1C.[H][C@@]12CN(C)C[C@]1(C)C[C@@H]2N.[H][C@@]12CN(C)C[C@]1([H])[C@H]2N MJKLCALMCCHQBO-MHRMMSPVSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 229920000297 Rayon Polymers 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- XUBOMFCQGDBHNK-UHFFFAOYSA-N gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCNC(C)C1 XUBOMFCQGDBHNK-UHFFFAOYSA-N 0.000 description 1
- 229960003923 gatifloxacin Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- CGRKYEALWSRNJS-UHFFFAOYSA-N sodium;2-methylbutan-2-olate Chemical compound [Na+].CCC(C)(C)[O-] CGRKYEALWSRNJS-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the invention relates to a process for preparing 8-methoxy-quinolonecarboxylic acids.
- 8-Methoxy-quinolonecarboxylic acids are antibiotics having potent antibacterial action against Gram-negative and Gram-positive bacteria.
- the antibiotics 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (INN: gatifloxacin, EP-A-230 295) and 1-cyclopropyl-7-[S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolonecarboxylic acid hydrochloride monohydrate (Bay 12-8039, EP-A-0 350 733) have a methoxy group in the 8-position.
- Such highly potent antibacterial quinolonecarboxylic acids usually have a heteromonocyclic or heteropolycyclic amine radical in the 7-position of the quinolonecarboxylic acid.
- This cyclic amine radical is generally prepared by nucleophilic substitution of the corresponding 7-halogeno-quinolonecarboxylic acid with the respective amine.
- the 8-alkoxy group can be introduced before the introduction of the cyclic amine radical in the 7-position, or afterwards.
- EP-A-0 350 733 describes the preparation of the racemic betaine of the abovementioned Bay 12-8039, starting from the corresponding 8-methoxy compound whose preparation is described in EP-A-0 241 206 (Preparation 6), by nucleophilic substitution with the corresponding racemic amine.
- the preparation of the enantiomerically pure betaine of Bay 12-8039 starting from the 8-methoxy compound by nucleophilic substitution with the enantiomerically pure amine is described in EP-A-0 550 903 (Example 19).
- the synthesis route described therein requires complicated isolation and purification by column chromatography which is undesirable for industrial scale. The latter approach is also used in EP-A-0 591 808 (Example Z 19).
- Another way of introducing an 8-alkoxy substituent into the 7-amine-substituted quinolonecarboxylic acids consists in 8-alkoxy substitution after the cyclic amine substituent has been introduced into the 7-position of the corresponding 7,8-dihalogeno starting material.
- EP-A-0 106 489 describes the route of 8-methoxy substitution after introduction of the heterocyclyl substituent in the 7-position by reaction of the corresponding 8-fluoro compound in methanol in the presence of potassium tertbutoxide.
- the reaction which is carried out in this publication with the 7-[2-[(methylamino)-methyl]-4-thiazole] compound requires 24 hours under reflux and is therefore unsuitable for a reaction on an industrial scale.
- certain quinolonecarboxylic acids such as, for example, the Bay 12-8039 described above, can not be prepared by this route since no reaction takes place under the conditions of the conversion under reflux for 24 hours.
- EP-A-02 30 295 likewise describes the route of 8-alkoxy substitution starting from 8-halogeno-7-monocycloamine derivatives in methanol in the presence of alkali metal alkoxides.
- the reaction in the presence of sodium methoxide described in the examples of this publication requires very high temperatures of approximately 140 to 150° C. and very long reaction times, and the reaction is carried out in closed vessels under pressure.
- this process is not generally applicable for preparing 8-methoxy-quinolonecarboxylic acids.
- application of this process for preparing the above-described Bay 12-8039 does not lead to formation of end product even after 70 hours if the solvent used is MeOH.
- preparation of the 8-alkoxy derivatives in EP-A-0 235 762 is carried out by reacting the 8-halogeno-7-monocycloamine derivatives with alkali metal alkoxides.
- preparation of 8-methoxy-quinolonecarboxylic acids by reacting the alkali metal alkoxides in solvents such as DMI (WO 93/22308, Chugai), with sodium methoxide in DMF or DMSO (EP-A-0 342 675, Chugai), with benzyl alcohol/sodium hydride (Research Disclosure No. 291 097, 1988), with sodium methoxide in DMF at 80° C.
- the invention accordingly, provides a process for preparing compounds of the formula in which
- the group forms a mono- or bicyclic heterocycle which may optionally contain in all ring moieties further nitrogen, oxygen or sulphur hetero-atoms and which may optionally be substituted.
- the ring members R′ and R′′ may represent identical or different ring components.
- Such mono- or bicyclic amine radicals in the 7-position of the quinolonecarboxylic acid skeleton are known in principle in the field of the quinolonecarboxylic acid antibiotics.
- EP-A-0 523 512 EP-A-0 230 295, EP-A-0 705 828, EP-A-0 589 318, EP-A-0 357 047, EP-A-0 588 166, GB-A-2 289 674, WO 92/09 579, JP-03-007 283, EP-A-0 241 206, EP-A-0 342 675, WO 93/22 308 and EP-A-0 350 733 may be mentioned.
- R 5 represents hydrogen or C 1 -C 3 -alkyl
- the aliphatic or cycloaliphatic ether having 4 to 6 carbon atoms is preferably selected from the group consisting of dimethoxyethane, dioxane and tetrahydrofuran.
- Hal preferably represents fluorine.
- the (C 1 -C 3 )-alkanol is preferably methanol, i.e. the process is preferably used for preparing the 8-methoxy compound.
- M is preferably potassium, i.e. the reaction is preferably carried out using potassium tert-butoxide or potassium tert-amylate, particularly preferably using potassium tert-butoxide.
- the reaction is preferably carried out between 20° C. and the boiling point of the solvent at atmospheric pressure.
- the process is preferably carried out in dimethoxyethane, dioxane, tetrahydrofuran or mixtures of these.
- the process is carried out in tetrahydrofuran as solvent.
- the (C 1 -C 3 )-alkanol is preferably methanol, i.e. the 8-methoxy compound is prepared (Bay 12-8039).
- M is preferably potassium.
- the process is preferably carried out between 20° C. and the boiling point of the solvent at atmospheric pressure.
- the process of the present invention is particularly suitable for preparing Here, is reacted with methanol and preferably potassium tert-butoxide in tetrahydrofuran as solvent.
- a particular advantage of the process according to the invention consists in the fact that preparation of pharmaceutically acceptable salts, for example the hydrochlorides, of the above-described compounds succeeds in a particularly simple manner by admixing the resulting reaction mixture with dilute hydrochloric acid or by adding the reaction mixture to dilute hydrochloric acid and isolating the salt, preferably the hydrochloride, by filtration.
- This immediate preparation of the hydrochloride is preferably employed for preparing the compound of the following formula:
- the compound described above (Bay 12-8039, hydrochloride) can surprisingly be isolated in high purity by recrystallization from water or a water/(C 1 -C 3 )-alkanol mixture.
- the purity of the compound obtained in this manner is already sufficient for many pharmaceutical applications.
- the recrystallization is preferably carried out from water or a water/ethanol mixture.
- (C 1 -C 3 )-alkyl or -alkyl radicals generally represent, for example, methyl, ethyl, propyl, isopropyl.
- (C 1 -C 3 )-alkyl and the (C 1 -C 3 )-alkyl radical in the corresponding aliphatic radicals represents methyl.
- reaction solution is added dropwise over a period of 2 hours at approximately 20 to 22° C. After addition of approximately 9 ml, the mixture is seeded with Bay 12-8039. After the addition is complete, the mixture is stirred at 8° C. for 30 minutes. A suspension is formed. The suspension is filtered and the filter cake is washed first with 6 ml of water and then with 12 ml of ethanol and dried under reduced pressure at 50° C. This gives 8.6 g.
- the product can be purified and converted into the monohydrate using the procedure of Example 1.
- the moist solid (108.2 g) is suspended in 385 ml of water, stirred at 20 to 25° C. for 30 minutes, filtered off with suction and washed twice with 38 ml of water (poor filtration properties).
- the precipitated crystals are filtered off with suction and washed twice with 10 ml of methanol each time.
- the solid is dried under reduced pressure at 50° C. (21.1 g) and dissolved under reflux in 68 ml of ethanol and 34 ml of water. After cooling to 20 to 25° C., the mixture is stirred for one hour and the precipitated crystals are filtered off with suction and washed twice with 10 ml of ethanol. Drying under reduced pressure at 50° C. gives 16.2 g of orange crystals.
- the process according to the invention thus offers, in particular on an industrial scale, enormous advantages in terms of yield, reaction time and work-up.
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- Engineering & Computer Science (AREA)
- Agronomy & Crop Science (AREA)
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- Zoology (AREA)
- Pest Control & Pesticides (AREA)
- Environmental Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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- Quinoline Compounds (AREA)
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Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19751948.2 | 1997-11-24 | ||
| DE19751948A DE19751948A1 (de) | 1997-11-24 | 1997-11-24 | Verfahren zur Herstellung von 8-Methoxy-Chinoloncarbonsäuren |
| PCT/EP1998/007237 WO1999026940A2 (de) | 1997-11-24 | 1998-11-12 | Verfahren zur herstellung von 8-methoxy-chinoloncarbonsäuren |
| DE10046267.7 | 2000-09-19 |
Related Parent Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US09554985 Continuation | 1998-11-12 | ||
| PCT/EP1998/007237 Continuation WO1999026940A2 (de) | 1997-11-24 | 1998-11-12 | Verfahren zur herstellung von 8-methoxy-chinoloncarbonsäuren |
| US55498500A Continuation | 1997-11-24 | 2000-05-23 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US11/127,811 Division US7115744B2 (en) | 1997-11-24 | 2005-05-11 | Method for producing 8-methoxy-quinolinecarboxylic acids |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| US20030208069A1 US20030208069A1 (en) | 2003-11-06 |
| US6897315B2 true US6897315B2 (en) | 2005-05-24 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US10/406,129 Expired - Lifetime US6897315B2 (en) | 1997-11-24 | 2003-04-03 | Method for producing 8-methoxy-quinolinecarboxylic acids |
| US11/127,811 Expired - Lifetime US7115744B2 (en) | 1997-11-24 | 2005-05-11 | Method for producing 8-methoxy-quinolinecarboxylic acids |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US11/127,811 Expired - Lifetime US7115744B2 (en) | 1997-11-24 | 2005-05-11 | Method for producing 8-methoxy-quinolinecarboxylic acids |
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Families Citing this family (21)
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| US6608078B2 (en) | 2000-05-08 | 2003-08-19 | Wockhardt Limited | Antibacterial chiral 8-(substituted piperidino)-benzo [i,j] quinolizines, processes, compositions and methods of treatment |
| US7098219B2 (en) | 2000-08-01 | 2006-08-29 | Wockhart Limited | Inhibitors of cellular efflux pumps of microbes |
| US6964966B2 (en) | 2001-04-25 | 2005-11-15 | Wockhardt Limited | Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments |
| US6878713B2 (en) | 2001-04-25 | 2005-04-12 | Wockhardt Limited | Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments |
| WO2003099815A1 (en) | 2002-05-28 | 2003-12-04 | Wockhardt Limited | Crystalline fluoroquinolone arginine salt form |
| ATE439840T1 (de) * | 2003-04-09 | 2009-09-15 | Reddys Lab Ltd Dr | Kristalline form iii von wasserfreiem moxifloxacin-hydrochlorid und ein verfahren zu seiner herstellung |
| EP1651630A1 (en) * | 2003-08-05 | 2006-05-03 | Matrix Laboratories Ltd | An improved process for the preparation of moxifloxacin hydrochloride |
| WO2005023805A1 (en) | 2003-09-04 | 2005-03-17 | Wockhardt Limited | Benzoquinolizine-2-carboxylic acid arginine salt tetrahydrate |
| ITMI20032259A1 (it) * | 2003-11-20 | 2005-05-21 | Chemi Spa | Nuovo polimorfo dell'acido 1-ciclopropil-7-(s,s-2,8-diazabciclo-4.3.0-non-8-il)-6-fluoro-1,4-diidro-8-metossi-4-oxo-chinolin carbossilico cloridrato e metodi per la sua preparazione |
| US7759362B2 (en) * | 2004-04-21 | 2010-07-20 | Institut Of Medicinal Biotechnology Chinese Academy Of Medical Sciences | Quinolonecarboxylic acid compounds, preparation methods and pharmaceutical uses thereof |
| WO2006134491A2 (en) * | 2005-06-14 | 2006-12-21 | Aurobindo Pharma Limited | New crystalline form of moxifloxacin hydrochloride and process for its preparation |
| ES2311391B1 (es) * | 2007-02-07 | 2009-12-22 | Quimica Sintetica, S.A. | Forma cristalina de moxifloxacino base. |
| EP2154137A1 (en) | 2008-08-04 | 2010-02-17 | Chemo Ibérica, S.A. | Crystalline form of moxifloxacin base |
| IT1393337B1 (it) | 2009-03-06 | 2012-04-20 | Italiana Sint Spa | Sintesi di (4as, 7as)-ottaidro-1h-pirrolo[3,4-b]piridina |
| IT1398952B1 (it) | 2010-03-19 | 2013-03-28 | F S I Fabbrica Italiana Sint | Processo di preparazione della moxifloxacina e suoi sali |
| CN102030751B (zh) * | 2010-12-01 | 2012-11-21 | 上虞京新药业有限公司 | 一种盐酸莫西沙星的结晶工艺 |
| CN104370906A (zh) * | 2014-11-17 | 2015-02-25 | 安徽美诺华药物化学有限公司 | 氟喹诺酮衍生物的制备方法 |
| CN104370907A (zh) * | 2014-11-17 | 2015-02-25 | 安徽美诺华药物化学有限公司 | 喹诺酮衍生物的制备方法 |
| CN104447741A (zh) * | 2014-11-17 | 2015-03-25 | 安徽美诺华药物化学有限公司 | 一种氟喹诺酮衍生物的制备方法 |
| CN104447742A (zh) * | 2014-11-17 | 2015-03-25 | 安徽美诺华药物化学有限公司 | 一种喹诺酮衍生物的制备方法 |
| CN111771895B (zh) * | 2020-08-03 | 2025-04-25 | 广西田园生化股份有限公司 | 喹诺酮类化合物在防治植物细菌性病害柑橘溃疡病上的新用途 |
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